CRCNS:Comput./Exp.Study:Hypothal.-Pituitary Interaction

描述（由申请人提供）：本项目的总体目标是将实验研究与数学建模相结合，以了解下丘脑和垂体之间的相互作用，导致催乳素激素的节律性分泌。这项工作将在实验实验室和数学建模实验室的密切合作下完成；这两个实验室位于同一所大学，促进了日常的互动。本研究的主要目的是了解下丘脑内的神经分泌细胞如何与脑垂体相互作用，从而在怀孕期间产生大鼠泌乳素分泌的日常节律。催乳素是哺乳动物中用途最广泛的激素之一，具有300多种不同的生物活性。在交配刺激后分泌的催乳素有许多目标，包括其他内分泌腺体，对维持大鼠正常妊娠很重要。催乳素是由垂体乳营养体分泌的。这些细胞的分泌受到下丘脑的严格控制，下丘脑是大脑的一个区域，负责将一天中的时间信息传递给身体的其他部分。下丘脑神经元与乳营养菌之间的相互作用是复杂的；神经元和乳营养物质相互影响，乳营养物质分泌的催乳素反馈并影响下丘脑神经元。这样一个复杂的系统是理想的数学建模，它可以提供洞察各种网络相互作用的影响，并可以用作集成信息的工具。在这个项目中，数学建模与实验研究相结合。该模型将通过实验数据进行校准，并将做出预测，并将在实验室进行测试。这种联合实验-计算方法非常适合于理解复杂的下丘脑-垂体网络。学生培训是这个项目的重要组成部分。预计研究生和博士后将在本文所述的研究中发挥非常积极的作用。这种参与将提供多学科的培训，这对日益多学科的工作场所是非常宝贵的。这项建议有四个具体目标。首先，建立垂体型乳养菌的数学模型。该模型主要基于我们实验室培养的乳营养菌的实验数据，将提供对这些细胞活动模式的机制理解。它还将用于了解多巴胺和催产素等激素如何改变这种活动。其次，将利用我们实验室的下丘脑切片数据，建立下丘脑多巴胺和催产素分泌神经元的数学模型。这些神经分泌细胞调节乳营养体分泌催乳素，并受视交叉上核（SCN）内神经元的影响。第三个具体目标是建立各种下丘脑神经元和垂体乳营养物之间网络相互作用的数学模型。这个模型将是最小的，专注于细胞之间的网络相互作用，而不是细胞内发生的详细的生物物理过程（前两个目标的目标）。第四，节律钟基因表达在多巴胺和催产素分泌神经元中的作用将被研究。如果表达模式被证明是有节奏的，那么这表明这些细胞向垂体提供昼夜节律输入，垂体与SCN内的神经元分离，但可能被其携带。这些研究将通过建立正常大脑在没有药物滥用的情况下支持脑下垂体功能的方式来支持NIDA的使命。这将导致滥用药物对脑垂体功能影响的研究。

DESCRIPTION (provided by applicant): The overall aim of this project is to combine experimental studies with mathematical modeling to understand the interactions between the hypothalamus and the pituitary gland that lead to rhythmic secretion of the hormone prolactin. This work will be done in close collaboration between an experimental lab and a mathematical modeling lab; both labs reside at the same university, facilitating daily interactions. The primary goal of this research is to understand how neurosecretory cells within the hypothalamus interact with the pituitary gland to produce daily rhythms of prolactin secretion in the rat during pregnancy. Prolactin is one of the most versatile hormones of mammalian organisms, with over 300 separate biological activities. The prolactin secreted following the mating stimulus has many targets, including other endocrine glands, and is important for maintaining a normal pregnancy in the rat. Prolactin is secreted by pituitary lactotrophs. Secretion from these cells is tightly regulated by the hypothalamus, a region of the brain that transmits time-of-day information to the rest of the body. The interaction between hypothalamic neurons and lactotrophs is complex; the neurons influence each other as well as the lactotrophs, and prolactin from lactotrophs feeds back onto and influences the hypothalamic neurons. Such a complex system is ideal for mathematical modeling, which can provide insight into the influence of the various network interactions, and can be used as a tool for integrating information. In this project, mathematical modeling is combined with experimental studies. The model will be calibrated by experimental data, and will make predictions that will be tested in the laboratory. This joint experimental-computational approach is well suited for understanding the complex hypothalamus-pituitary network. Student training is an important element of this project. It is anticipated that graduate students and postdoctoral fellows will play very active roles in the research described herein. This participation will provide multi-disciplinary training that will be invaluable for an increasingly multi-disciplinary workplace. There are four specific aims in this proposal. First, a mathematical model will be developed for pituitary lactotrophs. This model, based largely on experimental data on cultured lactotrophs from our lab, will provide a mechanistic understanding of the activity patterns of these cells. It will also be used to understand how the activity is modified by hormones such as dopamine and oxytocin. Second, mathematical models will be developed of hypothalamic dopamine- and oxytocin-secreting neurons, using hypothalamus slice data from our lab. These neurosecretory cells regulate prolactin secretion from lactotrophs, and are themselves under the influence of neurons within the suprachiasmatic nucleus (SCN). The third specific aim is to develop a mathematical model of the network interactions among the various hypothalamic neurons and pituitary lactotrophs. This model will be minimal, focusing on the network interactions between cells rather than the detailed biophysical processes that take place within cells (the goal of the first two aims). Fourth, the role of rhythmic clock gene expression in dopamine- and oxytocin-secreting neurons will be investigated. If the expression patterns are shown to be rhythmic, then this suggests that these cells provide circadian input to the pituitary that is separate from, but may be entrained by, neurons within the SCN. These studies will support the mission of NIDA by establishing the way the normal brain functions in the absence of drugs of abuse to support the pituitary gland. It will then lead to studies of effects of drugs of abuse on brain-pituitary function.